Structural and Functional Studies of Mammalian Peptidoglycan Recognition Protein, PGRP-S

Peptidoglycan recognition proteins belong to a broad family of innate immunity molecules. Mammals have four types of peptidoglycan recognition proteins designated as PGRP-S, PGRP-Iα, PGRP-Iβ and PGRP-L. PGRP-S is expressed in the granular polymorphonuclear leucocytes, PGRP-Iα is secreted from liver into blood and PGRP-Iβ, and PGRP-L are expressed in the skin, eyes, salivary glands, throat, tongue, esophagus, stomach and intestine. Peptidoglycan recognition proteins protect the host by carrying out early recognition of invading microorganisms. They contain a common domain known as peptidoglycan recognition domain whose lengths in various PGRPs vary from 165 to 175 residues. PGRP-S consists of a single peptidoglycan recognition domain while PGRP-Iα, PGRP-Iβ and PGRP-L have additional domains. Thus, PGRP-S represents the binding component of peptidoglycan recognition proteins and for understanding the mode of binding of these proteins, structural studies of PGRP-S are essential. So far, two structures of PGRP-S, one from human and another from Camelus dromedarius are available. The structure of human PGRP-S is found to be in monomeric state while the structure of camel PGRP-S consists of two distinct dimers in which dimeric interfaces involve opposite faces of the monomer. The observed monomeric and double dimeric structures of PGRP-S are well correlated to the differences in amino acid sequences of human and camel proteins. The binding sites in the dimers of camel PGRP-S are located at the contact sites of two molecules, whereas in human PGRP-S, it is supported by the single molecule. As a result, the binding clefts in camel protein are formed more efficiently as compared to the human protein. However, tertiary structures of both camel and human proteins are almost identical, with an average root mean squares shift of 1.2 A for the backbone atoms. Since the ligand binding clefts in camel protein appear to have been evolved with better binding potencies than the human protein, the camel PGRP-S could be exploited for beneficial therapeutic applications against bacterial infections.